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Second-generation methylthioadenosine (MTA)-cooperative PRMT5 inhibitors preferentially target MTAP-null cells while largely sparing MTAP-wildtype (MTAP-WT) cells, thereby improving tumor selectivity over first-generation PRMT5 inhibitors. Despite encouraging efficacy and safety signals in early clinical studies, the modest objective response rates (ORRs) observed with these inhibitors suggest that intrinsic or acquired resistance may limit their clinical benefit. Here, we investigated acquired resistance to the MTA-cooperative PRMT5 inhibitor BMS-986504\/MRTX1719 in MTAP-null non-small cell lung cancer (NSCLC) cells and sought to identify therapeutic vulnerabilities that emerge upon resistance. Using multiple in vitro-derived resistant models, we found that acquired resistance was accompanied by cross-resistance to mechanistically distinct PRMT5 inhibitors. Notably, this phenotype was not fully explained by altered PRMT5 activity or changes in MTA levels. High-throughput drug screening of paired sensitive and resistant cells revealed increased sensitivity to MEK inhibitors following acquisition of MRTX1719 resistance in KRAS-wildtype NSCLC cells. Consistently, resistant cells exhibited rewired MAPK-related transcriptional programs. Together, these findings identify MEK inhibition as a reproducible collateral vulnerability associated with acquired MRTX1719 resistance in MTAP-null NSCLC models and support further evaluation of MEK inhibition as a potential treatment-switching strategy following resistance.<\/jats:p>","DOI":"10.3390\/biom16081198","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T10:04:36Z","timestamp":1786961076000},"page":"1198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Acquired Resistance to the PRMT5 Inhibitor Confers Collateral Sensitivity to MEK Inhibition in MTAP-Null Non-Small Cell Lung Cancer"],"prefix":"10.3390","volume":"16","author":[{"given":"Rongjie","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9557-9101","authenticated-orcid":false,"given":"Yalong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6716-8287","authenticated-orcid":false,"given":"Ishita","family":"Rehman","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA"},{"name":"Department of Biotechnology, The Neotia University, Sarisha 743368, West Bengal, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ella","family":"Bedford","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9886-9130","authenticated-orcid":false,"given":"Sana","family":"Sharif","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, The University of Houston College of Pharmacy, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9379-5401","authenticated-orcid":false,"given":"Nghi D.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Texas A&M Health Center for Translational Cancer Research, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reid T.","family":"Powell","sequence":"additional","affiliation":[{"name":"Texas A&M Health Center for Translational Cancer Research, Houston, TX 77030, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"He","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5445-0443","authenticated-orcid":false,"given":"Pooja Anil","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi Rodon","family":"Ahnert","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2524-6440","authenticated-orcid":false,"given":"Taiping","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyi","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Biology and Biochemistry, University of Houston, Houston, TX 77004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0657-6484","authenticated-orcid":false,"given":"Clifford C.","family":"Stephan","sequence":"additional","affiliation":[{"name":"Texas A&M Health Center for Translational Cancer Research, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1680-1561","authenticated-orcid":false,"given":"Xinli","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, The University of Houston College of Pharmacy, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Bedford","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8654-461X","authenticated-orcid":false,"given":"Han","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA"},{"name":"Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5606","DOI":"10.1038\/s41467-021-25894-9","article-title":"9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy","volume":"12","author":"Han","year":"2021","journal-title":"Nat. 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